Influence of GSH S-transferase on the mutagenicity induced by dichloromethane and 1,2-dichloropropane
Influence of GSH S-transferase on the mutagenicity induced by dichloromethane and 1,2-dichloropropane
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DOI：
10.1093/mutage/gex014
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发表时间：
2017-07-01
期刊：
影响因子：
2.7
通讯作者：
Totsuka, Yukari
中科院分区：
文献类型：
--
作者：
Akiba, Nozomi;Shiizaki, Kazuhiro;Totsuka, Yukari
已有研究表明，二氯甲烷(DCM)和1，2-二氯丙烷(DCP)与职业性胆管癌有关。二卤烷被谷胱甘肽S转移酶theta1(GSTT1)代谢活化，生成如上硫离子等产物。然而，GSTT1介导的这些二卤代烷的步骤是否与职业性胆管癌有关尚不清楚。在本研究中，我们利用表达GSTT1的鼠伤寒沙门氏菌TA100(TA100-GST)研究了GSTT1激活对DCM和1，2-DCP致突变性的影响。与空白对照(TA100-PCTC)相比，TA100-GST组DCM的致突变性显著增强，推测GSTT1参与了DCM的致突变作用。HisG基因突变谱分析显示，DCM处理的TA100-PCTC以C：G到A：T转换为主。然而，在TA100-GST中，C：G到T：A的转变显著增加。我们还分析了DCM-DNA加合物N-2-GSH-Me-DG，与TA100-PCTC相比，TA100-GST中N-2-GSH-Me-DG的形成增加。另一方面，1，2-DCP不增加TA100-GSTT1的回复突变体数量。在突变谱分析中，TA100-PCTC和TA100-GSTT1均以C：G到T：A转换为主。这些发现表明，GSTT1在DCP的致突变性中几乎没有参与，其他机制可能对生物激活和随后的遗传毒性更重要。阐明DCM和/或1，2-DCP相关的人类胆管细胞癌的发生机制可能有助于建立职业性癌症的风险评估和预防策略。
It has been suggested that dichloromethane (DCM) and 1,2-dichloropropane (DCP) are responsible for occupational cholangiocarcinoma. Dihaloalkanes are metabolically activated by GSH S-transferase theta1 (GSTT1) to yield products such as episulfonium ions. However, whether the GSTT1-mediated step of these dihaloalkanes is related to occupational cholangiocarcinoma is not known. In the present study, we investigated the influence of GSTT1 activation on the mutagenicity of DCM and 1,2-DCP using GSTT1-expressing Salmonella typhimurium TA100 (TA100-GST). Since the mutagenicity of DCM was significantly increased in TA100-GST compared with mock control (TA100-pCTC), GSTT1 is thought to be involved in the mutagenicity of DCM. Mutation spectrum analysis on the hisG gene revealed that C:G to A:T transversions were the predominant form observed in DCM-treated TA100-pCTC. However, C:G to T:A transitions were dramatically increased in TA100-GST. We also analysed the DCM-DNA adduct, N-2-GSH-Me-dG, and formation of N-2-GSH-Me-dG was increased in TA100-GST compared with TA100-pCTC. On the other hand, 1,2-DCP did not increase the numbers of revertants in TA100-GSTT1. In mutation spectrum analysis, C:G to T:A transitions was predominant in both TA100-pCTC and TA100-GSTT1. These findings suggest that GSTT1 has little involvement in DCP mutagenicity, and other mechanisms might be more important for bioactivation and consequent genotoxicity. Clarification of the mechanisms underlying the development of DCM- and/or 1,2-DCP-related human cholangiocarcinoma may help establish risk assessment and prevention strategies against occupational cancer.